DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 02/06/2026 has been entered.
Election/Restrictions
Applicant has previously elected with traverse Group I, drawn to a method of engrafting airway basal cells
into the respiratory tract of a subject in need thereof, the method comprising removing epithelial cells from the
respiratory tract and administering airway basal cells to the respiratory tract. Claims 1-6, 8-20, 22-29, and 31-33 were pending and under consideration. Claims 1, 28, 29, 31, and 33 are currently amended. Claims 1-6, 8-20, 22-29, and 31-33 are under examination in the instant application.
Status of Prior Rejections/Response to Arguments
RE: Rejection of claim 31under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite:
Applicants’ amendments filed on 12/10/2025 overcome the indefiniteness rejection of claim 31. Applicants have specifically amended claim 31 to depend from claim 18, such that there is sufficient antecedent basis for the limitations “the chemical” and “the surgery” in the claim. The rejection is therefore withdrawn.
RE: Rejection of claims 1, 8, 10-20, 22-29 are rejected under 35 U.S.C. 103 as being unpatentable over HAWKINS et al., in view of Kwon et al.:
Applicants’ amendments and arguments filed on 12/10/2025 with respect to the rejection of claims 1, 8, 10-20, 22-29 have been considered and are effective to overcome the rejection of the claims. Applicants have specifically amended independent claims 1, 28, and 29 to claim that the airway basal cells are administered to the respiratory tract of the same subject from which the epithelial cells are removed. Also, applicants have specifically argued that such removal of epithelial cells, also referred to as denudation, can expose the basement membrane underlaying the epithelial cells and allow for successful engraftment of airway basal cells. However, Kwon et al.’s aims are not for treatment of a live subject, but rather, to isolate homogeneous cell samples for laboratory studies and a PHOSIOTA would not expect the ex vivo method of Kwon to translate to in vivo in a subject, nor would they be motivated to combine the teachings of Kwon, directed to ex vivo studies of whole-genome DNA methylation patterns, with the teachings of Hawkins, a method of treating disease, in the same subject and in the claimed order of steps.
Applicants’ amendments have been considered and are persuasive. The rejection is therefore withdrawn. However, in view of applicants’ amendments, a new ground(s) of rejection is made in view of Ma et al. (please see below the new rejection under Claim Rejections - 35 USC § 102).
RE: Rejection of claims 1-6 under 35 U.S.C. 103 as being unpatentable over HAWKINS et al., in view of
Kwon et al. and further in view of Farrow et al.:
Applicants have traversed the rejection asserting that independent claim 1 has been amended to claim that the airway basal cells are administered to the respiratory tract of the same subject from which the epithelial cells are removed. Also, applicants have specifically argued that although Farrow et al. allegedly alleviates the deficiency that the epithelial cells are removed from the respiratory tract using a chemical agent, Farrow et al. fails to relieve the deficiencies of Hawkins and Kwon, as discussed above related to removal of the epithelial cells in at least one bronchus and/or at least one bronchiole of a subject.
Regarding applicants’ arguments that Farrow et al. fails to teach that the epithelial cells are removed in at least one bronchus and/or at least one bronchiole of a subject, this is not persuasive because Farrow et al. was only used to cure the deficiency that the epithelial cells are removed from the respiratory tract using a chemical agent. However, upon further consideration and in view of applicants’ amendments to independent claim 1, a new ground(s) of rejection is made in view of Ma et al. (please see below the new rejection under Claim Rejections - 35 USC § 103).
RE: Rejection of claims 1 and 9 under 35 U.S.C. 103 as being unpatentable over HAWKINS et al., in view of Kwon et al., and further in view of Cleveland Clinic:
Applicants have traversed the rejection asserting that Cleveland Clinic fails to teach that the epithelial cells are removed in at least one bronchus and/or at least one bronchiole of a subject, this is not persuasive because Cleveland Clinic was only used to cure the deficiency of administering the airway basal cells using a bronchoscope. However, upon further consideration and in view of applicants’ amendments to independent claim 1, a new ground(s) of rejection is made in view of Ma et al. (please see below the new rejection under Claim Rejections - 35 USC § 102).
RE: Rejection of claims 1, 16, 29, 31, and 32 under 35 U.S.C. 103 as being unpatentable over HAWKINS et al., in view of Kwon et al., and further in view of Jayalakshmi et al.:
Applicants have traversed the rejection asserting that Jayalakshmi et al. fails to teach that the epithelial cells are removed in at least one bronchus and/or at least one bronchiole of a subject, this is not persuasive because Jayalakshmi et al. was only used to cure the deficiency that the respiratory tract injury is associated with: inhalation of a chemical, wherein the chemical is an acid and/or a surgery, wherein the surgery is tracheal resection or lung lobectomy. However, upon further consideration and in view of applicants’ amendments to independent claim 1, a new ground(s) of rejection is made in view of Ma et al. (please see below the new rejection under Claim Rejections - 35 USC § 102).
RE: Rejection of claims 33 under 35 U.S.C. 103 as being unpatentable over HAWKINS et al., in view of Dimmer et al.:
Applicants’ amendments and arguments filed on 12/10/2025 with respect to the rejection of claim 33 have been considered and are effective to overcome the rejection of the claim. Applicants have specifically amended independent claim 33 to claim that the airway basal cells are administered to the respiratory tract of the same subject from which the epithelial cells are removed in at least one bronchus of the respiratory tract of that subject. Also, applicants have specifically argued that Dimmer et al. fails to teach that the epithelial cells are removed in at least one bronchus and/or at least one bronchiole of the same subject receiving the administered airway basal cells, this is not persuasive because Dimmer et al. was only used to cure the deficiency that the epithelial cells are removed from the respiratory tract using bronchial thermoplasty.
However, upon further consideration and in view of applicants’ amendments to independent claim 1, a new ground(s) of rejection is made in view of Ma et al. (please see below the new rejection under Claim Rejections - 35 USC § 103).
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 9 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre- AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 9 recites “wherein the chemical agent and/or the airway basal cells are administered using a bronchoscope”. There is insufficient antecedent basis for the limitation “the chemical agent” in the claim. There is no recitation of this limitation in claim 1, from which claim 9 depends. See MPEP 2173.05(e).
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1, 8-13, 15-18, 22-32 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ma et al. (Ma et al., "Regeneration of functional alveoli by adult human SOX9+ airway basal cell transplantation". Protein & Cell, Volume 9, Issue 3, March 2018, Pages 267–282).
Regarding claim 1, Ma et al. teaches a method of engrafting airway basal cells into the respiratory tract of a subject in need thereof (Abstract and page 271, column 2, paragraph 1 and page 277, column 1, paragraph 3, Methods), the method comprising:(a) removing epithelial cells from the respiratory tract of the subject (Abstract and page 268, column 2, paragraph 1, lines 1-5), wherein the epithelial cells are removed in at least one bronchus and/or at least one bronchiole of the respiratory tract (page 268, column 2, paragraph 1, lines 4-7); and (b) then administering airway basal cells to the respiratory tract of the subject (Abstract and page 271, column 1, paragraph 2, lines 1-5).
Regarding claim 8: Following discussion of claim 1 above, Ma et al. teaches the airway basal cells are administered to at least one bronchiole of the respiratory tract (Abstract and page 271, column 1, paragraph 2, lines 29-32).
Regarding claim 9: Following discussion of claim 1 above, Ma et al. teaches that the airway basal cells are administered using a bronchoscope (page 277, column 1, paragraph 3, Methods).
Regarding claim 10: Following discussion of claim 1 above, Ma et al. teaches that the cells are obtained from a biopsy (paragraphs 0114 and 0314). This reads on the airway basal cells are primary cells (Abstract and Figure 3, page 272).
Regarding claim 11: Following discussion of claim 1 above, Ma et al. teaches that the basal cells
are generated from induced pluripotent stem cells (page 268, column 1, paragraph 1, lines 10-14).
Regarding claim 12: Following discussion of claim 1 above, Ma et al. teaches that the airway
basal cells (BCs) express one or more markers selected from the group consisting of: Nkx2-1; tumor protein 63
(TP63); cytoskeletal protein keratin 5 (KRT5) (page 268, column 2, paragraph 1, lines 10-17).
Regarding claim 13: Following discussion of claim 1 above, Ma et al. teaches that the airway basal cells are autologous to the subject (page 268, column 1, paragraph 1, lines 10-14 and paragraph 3).
Regarding claim 15: Following discussion of claim 1 above, Ma et al. teaches that the cells are
derived from a healthy subject (page 270, column 1, last paragraph).
Regarding claim 16: Following discussion of claim 1 above, Ma et al. teaches that the cells are
derived from a subject that has a respiratory tract disease or a respiratory tract injury (page 270, column 1, last paragraph).
Regarding claim 17: Following discussion of claim 1 above, Ma et al. teaches that the respiratory tract disease is chronic obstructive pulmonary disease (COPD) (page 270, column 1, last paragraph).
Regarding claim 18: Following discussion of claim 1 above, Ma et al. teaches that the respiratory tract injury is associated with a surgery (page 270, column 1, paragraph 1).
Regarding claim 22: Following discussion of claim 1 above, Ma et al. teaches that the engrafted airway basal cells reconstitute the tissue-resident airway basal stem cell compartment in the respiratory tract of the subject (page 268, column 1, last paragraph).
Regarding claim 23: Following discussion of claim 1 above, Ma et al. teaches that the engrafted airway basal cells comprise at least 10% of the epithelium in the respiratory tract of the subject after the engraftment (page 268, column 2, paragraphs 1-2).
Regarding claim 24: Following discussion of claim 1 above, Ma et al. teaches that the engrafted airway basal cells persist for at least 2 years following the engraftment (Figure 7, page 276).
Regarding claims 25-26: Following discussion of claim 1 above, Ma et al. teaches that the engrafted airway basal cells exhibit self- renewal and/or multipotent differentiation capacity for at least 2 years following the engraftment, wherein the multipotent differentiation capacity comprises basal cells (page 271, column 1, paragraph 2).
Regarding claim 27: Following discussion of claim 1 above, Ma et al. teaches that the engrafted airway basal cells exhibit a transcriptome that is at least 80% identical to the transcriptome of endogenous airway epithelium cells (Figure 1, page 268, column 2, paragraph 2).
Regarding claim 28: Following discussion of claim 1 above, Ma et al. teaches a method of treating a respiratory tract disease, the method comprising:(a) removing epithelial cells from the respiratory tract of a subject in need thereof, wherein the epithelial cells are removed in at least one bronchus and/or at least one bronchiole of the respiratory tract; and(b) then administering an effective amount of airway basal cells to the respiratory tract of the subject, wherein the respiratory tract disease is COPD (Abstract and page 271, column 2, paragraph 1 and page 277, column 1, paragraph 3, Methods, page 271, column 1, paragraph 2, lines 1-5, and page 270, column 1, last paragraph).
Regarding claim 29: Following discussion of claim 1 above, Ma et al. teaches a method of treating a respiratory tract injury, the method comprising:(a) removing epithelial cells from the respiratory tract of a subject in need thereof, wherein the epithelial cells are removed in at least one bronchus and/or at least one bronchiole of the respiratory tract; and(b) then administering an effective amount of airway basal cells to the respiratory tract of the subject; wherein the respiratory tract injury is associated with surgery (Abstract and page 271, column 2, paragraph 1 and page 277, column 1, paragraph 3, Methods, page 271, column 1, paragraph 2, lines 1-5, and page 270, column 1, paragraph 1).
Regarding claim 31: Following discussion of claim 18 above, Ma et al. teaches that the surgery is lung lobectomy (page 270, column 1, paragraph 1).
Regarding claim 32: Following discussion of claim 29 above, Ma et al. teaches that the surgery is lung lobectomy (page 270, column 1, paragraph 1).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim(s) 1-6 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ma et al. (Ma et al., "Regeneration of functional alveoli by adult human SOX9+ airway basal cell transplantation". Protein & Cell, Volume 9, Issue 3, March 2018, Pages 267–282), in view of Farrow et al. (Farrow et al., “Epithelial disruption: a new paradigm enabling human airway stem cell transplantation”. Stem Cell Res Ther 9, 153 (2018), pages 1-8).
Regarding claim 1, the teachings of Ma et al. are set forth in detail above.
Regarding claim 2: Following discussion of claim 1 above, Ma et al. fails to teach that the epithelial cells are removed from the respiratory tract using a chemical agent.
However, Farrow et al. teaches that 4 μL of 2% the agent polidocanol (PDOC) in phosphate-buffered
saline was administered to the nasal airway of mice to disrupt the epithelium (Abstract, Methods). Farrow et al.
further teaches that PDOC treatment denudes the nasal or tracheal epithelium but spares basal cells (page 6, column
2, paragraph 2, lines 1-2). Polidocanol reads on a chemical agent. Farrow et al. also teaches that disrupting the epithelial cell layer using the agent polidocanol (PDOC) would facilitate effective transplantation of cultured stem cells in mouse nasal airways (Abstract, Background).
Therefore, it would have been prima facie obvious to one of the ordinary skills in the art before the
effective filing date of the claimed invention to have modified the method of Ma et al. and administered PDOC to the bronchial epithelium instead of using a bronchoscope with a reasonable expectation of success. One would have been motivated to have done so for the purpose of removing the epithelium cells from the respiratory tract before administering the airway basal cells with predictable results.
Regarding claim 3: Following discussion of claim 2 above, Polidocanol is known in the art as a synthetic,
non-ionic detergent.
Regarding claim 4: Following discussion of claim 2 above, Farrow et al. teaches that 4 μL of 2% the agent
polidocanol (PDOC) in phosphate-buffered saline was administered to the nasal airway of mice to disrupt the
epithelium (Abstract, Methods).
Regarding claim 5: Following discussion of claim 2 above, Farrow et al. teaches that 4 μL of 2% the agent
polidocanol (PDOC) in phosphate-buffered saline was administered to the nasal airway of mice to disrupt the
epithelium (Abstract, Methods).
Regarding claim 6: Following discussion of claim 1 above, Farrow et al. further teaches that at 2 or 24 h
after PDOC treatment, human airway basal cells were transplanted into the animals (Abstract, Methods).
Claim(s) 1, 14, 19-20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ma et al. (Ma et al., "Regeneration of functional alveoli by adult human SOX9+ airway basal cell transplantation". Protein & Cell, Volume 9, Issue 3, March 2018, Pages 267–282), in view of HAWKINS et al. (the US Patent Application Publication US20210254016A1, filed on 02/19/2021, and published on 08/19/2021).
Regarding claim 1, the teachings of Ma et al. are set forth in detail above.
Regarding claim 14: Following discussion of claim 1 above, Ma et al. fails to teach that the airway basal cells are engineered to reduce or prevent expression of at least one major histocompatibility complex (MHC) polypeptide to reduce immunogenicity of the airway basal cells.
However, HAWKINS et al. teaches that the airway basal cells (BCs) are genetically modified in which the cells comprise a genome that has been manipulated, e.g., by mutation, such as site-directed mutation (paragraphs 0049 and 0333). Site-directed mutation is a mutation that can reduce MHC expression. HAWKINS et al. further teaches in paragraphs 0115 and 0333 that such mutations result in a change in gene or protein expression relative to an un-modified cell. Introduction of RNA can transiently promote expression of a foreign or heterologous product, as can the introduction of a vector that does not integrate or replicate within the cell and such modification is to reduce the risk of engraftment rejection or immunogenicity of the cells.
Therefore, it would have been prima facie obvious to one of the ordinary skills in the art before the
effective filing date of the claimed invention to have modified the airway basal cells in the method of Ma et al. to reduce or prevent expression of MHC with a reasonable expectation of success. One would have been motivated to have done so in order to reduce immunogenicity of the airway basal cells as taught by HAWKINS et al.
Regarding claims 19 and 20: Following discussion of claim 1 above, HAWKINS et al. teaches mutations
of the CFTR gene affecting chloride ion channel function leads to dysregulation of epithelial fluid transport in the
lung, pancreas and other organs, resulting in cystic fibrosis (paragraph 0241). HAWKINS et al. further teaches that
the airway basal cell line is genetically modified to correct a genetic lesion or mutation in the CFTR gene that causes
cystic fibrosis (paragraph 0330). Correcting a mutation in the CFTR gene that causes cystic fibrosis reads on
expressing at least one functional polypeptide that is dysfunctional in a respiratory tract disease as recited in claim
19 and on expressing functional CFTR polypeptide as recited in claim 20. Additionally, HAWKINS et al. teaches
that mutations in DNAH5 have been associated with primary ciliary dyskinesia (PCD) and that the airway basal
cells described herein are genetically modified to correct a DNAH5 mutation (paragraph 0243, line 3 and last 2
lines). Correcting a mutation in the DNAH5 gene that causes primary ciliary dyskinesia reads on expressing
functional DNAH5 polypeptide.
Claim(s) 33 is rejected under 35 U.S.C. 103 as being unpatentable over Ma et al. (Ma et al., "Regeneration of functional alveoli by adult human SOX9+ airway basal cell transplantation". Protein & Cell, Volume 9, Issue 3, March 2018, Pages 267–282), in view of Dimmer et al. (US9662171B2, issued on 05/30/2017).
Regarding claim 33, Ma et al. teaches a method of engrafting airway basal cells into the respiratory tract of a subject in need thereof, the method comprising:(a) removing epithelial cells from the respiratory tract, wherein the epithelial cells are removed in at least one bronchus of the respiratory tract of the subject and (b) then administering airway basal cells to the respiratory tract of the subject (Abstract and page 271, column 2, paragraph 1 and page 277, column 1, paragraph 3, Methods and page 271, column 1, paragraph 2, lines 1-5).
However, Dimmer et al. teaches using bronchial thermoplasty to remove cells in the inner lining of the
airway wall, such as the epithelium. Dimmer et al. specifically teaches that heat can be concentrated in the inner
lining (e.g., the epithelium) of the airway wall (column 21, lines 66-67 and column 22, lines 1-2). Dimmer et al. also
teaches that treatments for pulmonary diseases, such as COPD and asthma, such as bronchial thermoplasty, involve
destroying cells by ablating the airway wall in a multitude of bronchial branches within the lung (column 3, lines 44-
48). Bronchial thermoplasty uses heat to reduce excess airway smooth muscle tissue, which minimizes the airway
constriction that takes place during an asthma attack. This reads on removing the epithelial cells from the respiratory
tract using bronchial thermoplasty.
Therefore, it would have been prima facie obvious to one of the ordinary skills in the art before the
effective filing date of the claimed invention to have modified the method of Ma et al. and removed the epithelium using bronchial thermoplasty to isolate the epithelial cells from the respiratory tract before administering the airway basal cells with a reasonable expectation of success. One would have been motivated to have done so to reduce excess airway smooth muscle tissue which minimizes the airway constriction and facilitate effective transplantation and enragement of the airway basal cells in the respiratory tract of said subject.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HANAN ISAM ABUZEINEH whose telephone number is (571)272-9596. The examiner can normally be reached Mon- Fri 8:30-5:00.
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Hanan Isam Abuzeineh
/H.I.A./Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633